Article 1
Open ↗1. The national competent authorities, the European Medicines Agency or the Commission may require a post-authorisation efficacy study to be carried out by the holder of a marketing authorisation in accordance with Articles 21a(f) and 22a(1)(b) of Directive 2001/83/EC and Articles 9(4)(cc) and 10a(1)(b) of Regulation (EC) No 726/2004: (a) where concerns relating to some aspects of efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed; (b) where the understanding of the disease, the clinical methodology or the use of the medicinal product under real-life conditions indicate that previous efficacy evaluations might have to be revised significantly. 2. The national competent authorities, the European Medicines Agency or the Commission shall only apply paragraph 1 if one or more of the following cases arise: (a) an initial efficacy assessment that is based on surrogate endpoints, which requires verification of the impact of the intervention on clinical outcome or disease progression or confirmation of previous efficacy assumptions; (b) in case of medicinal products that are used in combination with other medicinal products, the need for further efficacy data to clarify uncertainties that had not been addressed when the medicinal product was authorised; (c) uncertainties with respect to the efficacy of a medicinal product in certain sub-populations that could not be resolved prior to marketing authorisation and require further clinical evidence; (d) the potential lack of efficacy in the long term that raises concerns with respect to the maintenance of a positive benefit-risk balance of the medicinal product; (e) benefits of a medicinal product demonstrated in clinical trials are significantly affected by the use of the medicinal product under real-life conditions, or, in the case of vaccines, protective efficacy studies have not been feasible; (f) a change in the understanding of the standard of care for a disease or the pharmacology of a medicinal product that requires additional evidence on its efficacy; (g) new concrete and objective scientific factors that may constitute a basis for finding that previous efficacy evaluations might have to be revised significantly. 3. The situations set out in paragraph 1 and 2 are without prejudice to the imposition of the obligation on the holder of a marketing authorisation to conduct a post-authorisation efficacy study in the context of any of the following situations: (a) a conditional marketing authorisation granted in accordance with Article 14(7) of Regulation (EC) No 726/2004; (b) a marketing authorisation granted in exceptional circumstances and subject to certain conditions in accordance with Article 14(8) of Regulation (EC) No 726/2004 or Article 22 of Directive 2001/83/EC; (c) a marketing authorisation granted to an advanced therapy medicinal product in accordance with Article 14 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council ( 4 ) ; (d) the paediatric use of a medicinal product in accordance with Article 34(2) of Regulation (EC) No 1901/2006 of the European Parliament and of the Council ( 5 ) ; (e) a referral procedure initiated in accordance with Articles 31 or 107i of Directive 2001/83/EC or Article 20 of Regulation (EC) No 726/2004.